Characterization of a 8q21.11 microdeletion syndrome associated with intellectual disability and a recognizable phenotype.

We report eight unrelated individuals with intellectual disability and overlapping submicroscopic deletions of 8q21.11 (0.66-13.55 Mb in size). The deletion was familial in one and simplex in seven individuals. The phenotype was remarkably similar and consisted of a round face with full cheeks, a high forehead, ptosis, cornea opacities, an underdeveloped alae, a short philtrum, a cupid's bow of the upper lip, down-turned corners of the mouth, micrognathia, low-set and prominent ears, and mild finger and toe anomalies (camptodactyly, syndactyly, and broadening of the first rays). Intellectual disability, hypotonia, decreased balance, sensorineural hearing loss, and unusual behavior were frequently observed. A high-resolution oligonucleotide array showed different proximal and distal breakpoints in all of the individuals. Sequencing studies in three of the individuals revealed that proximal and distal breakpoints were located in unique sequences with no apparent homology. The smallest region of overlap was a 539.7 kb interval encompassing three genes: a Zinc Finger Homeobox 4 (ZFHX4), one microRNA of unknown function, and one nonfunctional pseudogen. ZFHX4 encodes a transcription factor expressed in the adult human brain, skeletal muscle, and liver. It has been suggested as a candidate gene for congenital bilateral isolated ptosis. Our results suggest that the 8q21.11 submicroscopic deletion represents a clinically recognizable entity and that a haploinsufficient gene or genes within the minimal deletion region could underlie this syndrome.

Prevention, diagnosis and services.

This chapter summarizes how prevention, diagnosis and services can result from the activities of a research programme on the group of rare diseases constituted by congenital anomalies. The Spanish Collaborative Study of Congenital Malformations (ECEMC) is a research programme based on a case-control registry of consecutive newborn infants with congenital anomalies. Its aim is the prevention of this group of rare diseases, through the research on their causes and pathogenesis, combined with the translational activity to transfer the benefits of this knowledge to the general population and health care providers. Its experience could be applied to the research on other rare diseases. The different levels of prevention (primary, secondary, tertiary and quaternary) are briefly defined, and the way in which these levels are being applied or can be applied to congenital defects prevention is reviewed. The main primary prevention measures regarding congenital anomalies are also detailed. To this respect, the benefits derived from the activity of Teratology Information Services (TIS), for the general population as well as for health care providers, are explained. It is finally emphasized how the epidemiological data can contribute to the prevention of that group of rare diseases.

Review of the recently defined molecular mechanisms underlying thanatophoric dysplasia and their potential therapeutic implications for achondroplasia.

Achondroplasia (ACH), thanatophoric dysplasia (TD) types I and II, hypochondroplasia (HCH), and severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN) are all due to activating mutations in the fibroblast growth factor receptor 3 (FGFR3) gene. We review the clinical, epidemiological, radiological, molecular aspects, and signaling pathways involved in these conditions. It is known that FGFR3 signaling is essential to regulate bone growth. The signal transducers and activators of transcription (STAT1) pathway is involved in the inhibition of chondrocyte proliferation, and the mitogen-activated protein kinase (MAPK) pathways are involved in chondrocyte differentiation. Hence, FGFR3 signaling is pivotal in chondrocyte differentiation and proliferation through these two different active pathways. Recent studies on the molecular mechanisms involved in chondrocyte differentiation and proliferation, demonstrated that Snail1 participates in the control of longitudinal bone growth and appears to be essential to transduce FGFR3 signaling during chondrogenesis. This result was confirmed in a newborn infant with TD, and suggests new non-surgical therapeutic approaches, that is, Snail1 as a new encouraging therapeutic target.

Epidemiological and clinical analysis of a consecutive series of conjoined twins in Spain.

PURPOSE: The aim of the study was to analyze the frequency and certain epidemiological characteristics of a consecutive series of conjoined twins born in Spain. MATERIAL AND METHODS: We used data from the Spanish Collaborative Study of Congenital Malformations for the period April 1976 to 2006. Because the Spanish law permitting voluntary termination of pregnancies (TOP) when the fetus presented malformations was effective by the end of 1985, we analyzed the data in 4 periods, 2 before 1986 and 2 after. During the first period (1976-1979) only live births were recorded, whereas both still and live births were included in the other three (1980-1985, 1986-1995, and 1996-2006). In the present study, the cases were classified as symmetrical (16 pairs) and asymmetrical (1 pair) conjoined twins. Each pair of conjoined twins was considered as only one case for calculations, regardless of the type of union. RESULTS: Among a total of 2,281,604 consecutive births between 1980 and 2006, there were a total of 15 cases of symmetrical conjoined twins giving a frequency of 0.70 per 100,000 (1/152,107), whereas there was only 1 stillborn asymmetrical conjoined twin pair (0.04/100,000). Among the 13,418 consecutive stillborns surveyed, 6 cases of conjoined twins were identified (either symmetrical or asymmetrical) giving a frequency of 44.72 per 100,000, and 11 pairs were identified among the 2,425,583 total live births surveyed during the first period 1976 to 1979, a frequency of 0.45 per 100,000. Thus, the frequency among stillborn infants is 99.34 times higher than that observed among live births. However, the frequency for the total births (3 last periods) showed a decreasing trend from 1.47 per 100,000 birth in the first period (1980-1985) when TOP was illegal, to a value of 0.09 per 100,000 in the last period, more than 16-fold lower, probably because of the TOP of affected fetuses. Therefore, we consider that the frequencies observed in the period 1980 to 1985 are the basal values in our population. The most frequent type observed was thoracopagus, with an overall prevalence at birth of 0.44 per 100,000 (1/228,160) from 1980 to 2006, representing 58.82% of the total population of symmetric conjoined twin pairs. Diprosopus pairs were the next most common group (11.76%). Most of the cases were females (4 males/11 females), and although this appeared to be mainly because of the thoracopagus pairs (males-females, 2:8), in such a small number of cases, it is not possible to determine the ratios for the other groups. Gestational age was significantly shorter than in control twins for each type studied. CONCLUSIONS: We conclude that it is incorrect to consider that all types of conjoined twins have the same epidemiological characteristics, such as the frequency at birth. The differences observed may be related with the distinct embryo-fetal mortality of each type of conjoined twins in different populations, and the sex ratio, among others.

[Alström syndrome: clinical and genetic features, and a diagnostic guide to foresee complications]. / Presentación de un caso con síndrome de Alström: aspectos clínicos, moleculares y guías diagnósticas y anticipatorias.

BACKGROUND AND OBJECTIVE: Alström syndrome is a progressive autosomal recessive genetic disorder affecting multiple organ systems. It may be detected at birth or in early childhood. Clinically, patients with Alström syndrome develop cone-rod dystrophy leading to eventual blindness, sensorineural deafness, and normal intelligence. Patients develop obesity, endocrine disturbances such as type 2 diabetes mellitus, dilated cardiomyopathy and progressive renal and hepatic failure. Alström syndrome is caused by specific mutations in the ALMS1 gene, located at chromosome 2p13. PATIENTS AND METHOD: A case of a 23 year old patient with Alström syndrome, with a previous diagnosis of Laurence-Moon-Bardet-Biedl is described. RESULTS: The subsequent molecular study revealed a mutation on the ALMS1 gene, confirming the diagnosis of Alström syndrome. CONCLUSIONS: The low frequency, the progressive multi-systemic disturbances, and the similarities with other well-known syndromes may difficult the diagnosis of Alström syndrome. Thus, without a careful examination, it may be misdiagnosed and it would not be possible to perform any anticipatory therapeutic approach, with dramatic consequences for the patients and their families. Moreover, as these patients must have a multidisciplinary approach, they may not receive the adequate treatment on time. therefore, it seems important to publish this case in our country, among with the clinical and molecular characteristics of this syndrome, and to spread a diagnostic and anticipatory guidance for its early detection.

Preferential associations between oral clefts and other major congenital anomalies.

OBJECTIVES: To identify preferential associations between oral clefts (CL = cleft lip only, CLP = cleft lip with cleft palate, CP = cleft palate) and nonoral cleft anomalies, to interpret them on clinical grounds, and, based on the patterns of associated defects, to establish whether CL and CLP are different conditions. DESIGN AND SETTINGS: Included were 1416 cleft cases (CL = 131, CLP = 565, CP = 720), among 8304 live- and stillborn infants with multiple congenital anomalies, from 6,559,028 births reported to the International Clearinghouse for Birth Defects Surveillance and Research by 15 registries between 1994 and 2004. Rates of associated anomalies were established, and multinomial logistic regressions applied to identify significant associations. RESULTS: Positive associations with clefts were observed for only a few defects, among which anencephaly, encephaloceles, club feet, and ear anomalies were the most outstanding. Anomalies negatively associated with clefts included congenital heart defects, VATER complex (vertebral defects, imperforate anus, tracheoesophageal fistula, and radial and renal dysplasia), and spina bifida. CONCLUSION: The strong association between all types of clefts and anencephaly seems to be attributable to cases with disruptions; the association between CP and club feet seems to be attributable to conditions with fetal akinesia. Some negative associations may depend on methodologic factors, while others, such as clefts with VATER components or clefts with spina bifida, may depend on biological factors. The different patterns of defects associated with CL and CLP, indicating different underlying mechanisms, suggest that CL and CLP reflect more than just variable degrees of severity, and that distinct pathways might be involved.

[Analysis of the frequencies of genotype combinations of 4 polymorphisms of genes acting on the folate cycle in the Spanish population]. / Análisis de las frecuencias de todas las combinaciones genotípicas de 4 polimorfismos de genes implicados en el ciclo del folato en la población española.

BACKGROUND AND OBJECTIVE: Studies on different populations have shown a great variability of the frequencies of different polymorphisms in genes acting in the folate cycle. The present study was aimed to analyze the frequency in the Spanish population of each genotype combination of four polymorphisms, one of them -1561C-T of the glutamate carboxypeptidase II (GCPII) gene- being the first time that is studied in Spain. The study included a meta-analysis of the published data. SUBJECTS AND METHOD: Using the Spanish Collaborative Study of Congenital Malformations (ECEMC) Network, blood samples of 190 mother-child couples with newborns without any congenital defect, were obtained from 15 Spanish autonomous regions. The study polymorphisms were the 677C-T and 1298A-C polymorphisms of the methylenetetrahydrofolate reductase (MTHFR), the 66A-G of the methionine synthase reductase (MTRR), and the 1561C-T polymorphism of the GCPII gene. To estimate the range for the population frequencies, 99% confidence intervals were calculated. RESULTS: The frequencies observed in our country were significantly different from others, being similar to those obtained in countries of the Mediterranean European area. The 1561C-T polymorphism of the GCPII gene has a frequency in Spain of 5.11%, which is also similar to the values observed in France (5%) and in Italy (6%). On the other hand, the frequency of the genotypes CTCC, TTAC is quite few, while the genotype TTCC was not observed in any mother or infants. A meta-analysis was performed for a big sample (23,612 individuals) and the results showed that with a 99% of probability the values for the genotype combinations CTCC, TTAC, and TTCC were within 0.10-0.24; 0.20-0.36; and 0.003-0.05, respectively. CONCLUSIONS: Our results are important to further analyze the relationship with some health problems and individual susceptibilities. Indeed, considering the published observations of the structure and function of the MTHFR enzyme, it is understandable that those genotype combinations that are quite little frequent, may be related to the embryo-fetal viability, and to the life style of each population.

Does single umbilical artery (SUA) predict any type of congenital defect? Clinical-epidemiological analysis of a large consecutive series of malformed infants.

Most studies associating different types of malformations with the presence of a single umbilical artery (SUA) are based on small and selected series. Here, we present the results of a study aimed at identifying the most frequent, and the most specific anomalies related to SUA. We analyzed 19,909 consecutive newborn infants with congenital malformations, from the Spanish Collaborative Study of Congenital Malformations (ECEMC). To estimate the specificity of the relationship of different congenital defects with SUA, we calculated their relative frequencies (RF) by dividing their frequency in infants with SUA by the corresponding frequency in newborn infants without SUA. Using the different levels of the ECEMC coding system, we calculated the RFs in three steps: (a) a group of individual congenital defects, (b) different groups of malformed infants, and (c) each individual malformation by its clinical presentation in some of the studied groups of malformed infants. The defects most specifically associated with SUA were bilateral renal agenesis and imperforate anus, followed by unilateral renal agenesis, and vertebral defects, the RF of which indicated that they were between 7.99 and 9.93 times more frequent among malformed infants with SUA than among malformed infants without SUA. However, these defects were not as frequent in the group of infants with SUA, as cardiovascular anomalies. Regarding the association of SUA in the groups of malformed infants, the most specific groups were body stalk defects and sirenomelia. Finally, we analyzed the association of the individual defects by different groups of malformed infants in order to identify if the individual defects are associated with SUA in any type of clinical presentation, and in relation to some groups of infants with genetic disorders. The results, together with the embryonic development of the umbilical cord, strongly suggest that not all cases of SUA have the same cause, and that all previously suggested mechanisms may be possible but with different frequencies.

Gastroschisis and associated defects: an international study.

Our objective was to evaluate the frequency and type of malformations associated with gastroschisis in a large pool of international data, to identify malformation patterns, and to evaluate the role of maternal age in non-isolated cases. Case-by-case information from 24 registries, all members of the International Clearinghouse for Birth Defects Surveillance and Research (ICBDSR), were evaluated. After the exclusion of other abdominal wall defects cases were classified as: (a) isolated; (b) recognizable syndrome, chromosomal or not; (c) multiple congenital anomalies (MCA). Our results showed that out of 3,322 total cases 469 non-isolated cases were registered (14.1%): 41 chromosomal syndromes, 24 other syndromes, and 404 MCA. Among MCA four groups of anomalies were most frequent: CNS (4.5%), cardio-vascular (2.5%), limb (2.2%), and kidney anomalies (1.9%). No similar patterns emerged except two patterns resembling limb-body wall complex and OEIS. In both of them the gastroschisis could be however misclassified. Chromosomal trisomies and possibly non-syndromic MCA are associated with an older maternal age more than isolated cases. On consideration of our data and the most valid studies published in the literature, the best estimate of the proportion of gastroschisis associated with major unrelated defects is about 10%, with a few cases associated to recognizable syndromes. Recognized syndromes with gastroschisis seem to be so exceptional that the well documented and validated cases are worth being published as interesting case report. An appropriate case definition in etiological studies should include only isolated gastroschisis after an appropriate definition of isolated and non-isolated cases and a thorough case-by-case review.

Pilot study of socioeconomic class, nutrition and birth defects in Spain.

Research has indicated that the appropriate intake of folic acid, a B vitamin, before and during early pregnancy has been shown to prevent 50-70% of neural-tube defects. Increased NTD incidence has long been reported to occur more frequently among women of lower socioeconomic (SES). Since consumption of the folate-rich Mediterranean diet in Spain does not vary by socio-economic status (SES), we hypothesized that there would be no social class effect on NTD occurrence. Using data from a Spanish hospital-based birth defects registry, we studied the risk of Neural Tube Defects (NTDs) in 980 cases and 774 controls between 1980 and 2003. Our analysis showed that the risk of NTDs did not vary by SES. This finding suggests that increased access to folate and nutrition education might benefit women of lower SES in the US.

[Dyggve-Melchior-Clausen syndrome: presentation of a case with a mutation of possible Spanish origin]. / Síndrome de Dyggve-Melchior-Clausen: presentación de un caso con una mutación de posible origen español.

BACKGROUND AND OBJECTIVE: The Dyggve-Melchior-Clausen syndrome is a progressive spondyloepimetaphyseal dysplasia characterized by a short trunk dwarfism, barrel chest, sternal protrusion, kyphoscoliosis, severe platyspondyly, with a central constriction, irregular iliac wings with a lacy appearance, rhizomelic shortening of the limbs, microcephaly, coarse face, and variable mental retardation. This condition is extremely rare and the diagnosis is difficult without any previous experience on it. It is inherited as an autosomal recessive condition, its gene (DYM) having been mapped in the 18q12-21.1 chromosomal region. At least 21 different mutations of this gene have been reported. MATERIAL AND METHODS: We describe an affected Spanish child and include his molecular analysis. We also review the current knowledge on this syndrome. RESULTS: The diagnosis of this patient, based on his clinical and radiological features, was later confirmed by analysis of the DYM gene mutations. The patient had two different mutations, one inherited from the mother and the other inherited from the father. CONCLUSIONS: One of the mutations of this patient (exon 8) is extremely rare and has mostly been reported in patients with Spanish ancestors (from Chile, Argentina, Guam islands and a French patient with Spanish ancestors). These observations, together with that of the patient described here, led us to consider this mutation as having a possible Spanish/Portuguese origin. This condition may be more frequent in Spain than previously thought, especially due to misdiagnosis. This is important in order to undertake quaternary prevention, which is quite necessary for rare syndromes with polysystemic affectation.

Maternal polymorphisms 677C-T and 1298A-C of MTHFR, and 66A-G MTRR genes: is there any relationship between polymorphisms of the folate pathway, maternal homocysteine levels, and the risk for having a child with Down syndrome?

This study was aimed at analyzing the effect of mutations in three non-synonymous SNP genes (677C > T and 1298A > C of the methylenetetrahydrofolate reductase (MTHFR) gene, and 66A > G in the MTRR gene) on total plasmatic homocysteine (Hcy), in 91 mothers of Down syndrome (DS) infants and 90 control mothers. The comparison of both groups of mothers is a new way to determine if those mutations and their interactions increase the risk for DS. Material came from the case-control network of the Spanish Collaborative Study of Congenital Malformations (ECEMC). Using a general lineal model in a backwards step, we performed the analyses including the different mutations, maternal age, the fact that each mother had a DS or a control infant, and all possible interactions of these variables, in the models, being maternal Hcy the continuous dependent variable. In another model, maternal folic acid intake during the third trimester of pregnancy was added. The results from both models were essentially the same: Hcy levels variability differs from case mothers to control ones, the presence of the MTHFR1298A > C polymorphism also affects significantly the Hcy variance, as it does the statistical interaction between the mutations MTRR66A > G and MTHFR1298A > C in the mother. In this sense, the interaction between different polymorphisms may totally modify their individual effects, and some of those effects are different in mothers of DS children and in controls' mothers. For instance, only two mutations in MTRR66 (GGAA) in mothers of control infants increase the reference maternal Hcy level in 4.66 units, and the individual effect of the genotype with only two mutations in the MTHFR1298 gene (AACC) increases the reference Hcy level in 12.74 units. However, the presence of the four mutations (GGCC) interacts giving a statistically significant decrease in 6.00 units in the level of Hcy in control mothers. On the contrary, in mothers of DS infants, the sole presence of two mutations in one of these two genes decreases the levels of Hcy (-2.31 units for GGAA genotype, and -3.43 units for AACC genotype), while the presence of the four mutations (GGCC) increases Hcy in 9.53 units. Taking into consideration that in the one-carbon metabolism cystathionine beta-synthase (CBS) catalyzes Hcy in an irreversible way, and that CBS gene is located in chromosome 21, fetuses and infants with DS have functional folate deficiency due to overexpression of CBS. This fact, as well as others influencing Hcy levels (such as nutrients interactions and lifestyle), together with the fetal genotype, suggest that their relationship with DS could be through an effect on fetal survival up to birth. Three possible mechanisms are considered by evaluating the results in the light of the present knowledge on cytology and molecular biology.

Growth deficiency, facial anomalies, and brachydactyly (Frías syndrome): a second family.

A second family with the condition first described by Frías et al. in 1975 is presented. Those authors examined a mother and her son affected with short stature, facial anomalies (epicanthic folds, downward palpebral fissures, hyperthelorism, and eyelid ptosis), cup-shaped and posteriorly rotated ears, hand and foot defects, and delayed bone age. In the family we are presenting here, a girl, her mother, the mother's brother, and the propositus' maternal grandmother, were affected. This supports autosomal dominant inheritance, as proposed by (Frías et al. [1975] BDOAS 11:30-33), although with variable expressivity.

Sensorineural deafness, abnormal genitalia, synostosis of metacarpals and metatarsals 4 and 5, and mental retardation: description of a second patient and exclusion of HOXD13.

In 1988 Pfeiffer and Kapferer reported on a patient with sensorineural deafness, psychomotor delay, hypospadias, cerebral manifestations, and bilateral synostosis of the 4th and 5th metacarpals and metatarsals. Synostosis of the 4th and 5th metacarpals and metatarsals is a very rare defect that has been described as an isolated Mendelian defect, as part of multiple congenital anomaly (MCA) patterns, and in different syndromes. Among a total of 2,023,155 liveborn infants in the Spanish Collaborative Study of Congenital Malformations (ECEMC), we observed only two cases with this type of metacarpal fusion, for a frequency of 1/1,011,577. One had the isolated defect, and the other one that we are describing here, had an MCA pattern similar to that described by Pfeiffer and Kapferer [1988]. We tested HOXD13 but did not find any mutations in exons and intron-exon boundaries. To our knowledge this case is the second one reported with this syndrome.

[Tobacco smoking during pregnancy in Spain: an analysis according to years, autonomous communities and maternal characteristics]. / Consumo de tabaco durante el embarazo en España: análisis por años, comunidades autónomas y características maternas.

BACKGROUND AND OBJECTIVE: The information about the convenience of non-smoking during pregnancy has increased in recent years. For this reason, we studied weather there has been any variation in smoking habits by pregnant women in Spain. SUBJECTS AND METHOD: We used data from 31,056 mothers of infants without congenital defects, from all the Spanish Autonomic Regions. These data had been collected with the same methodology all over the country. The evolution of maternal smoking habit was analyzed by years, Autonomic Regions and maternal characteristics. RESULTS: During the last years of the study (1995-2002), 30.31% of mothers smoked during pregnancy, with variations among different ethnic groups. It was observed a secular increase in the prevalence of smoker mothers from 1978 to 1991, which was further stable in about 27-28%. There was no secular decrease in the analyses by maternal age, number of cigarettes, and Autonomic Regions. Only smoker mothers with higher educational levels diminished smoking in 1993, with it being stable in about 23%. Mothers younger than 25 years were the heaviest smokers in all the years of the study. We confirmed a close relationship between tobacco, alcohol and illegal drugs consumption. CONCLUSIONS: Our data indicate that the prevalence of women smoking during pregnancy has not diminished over the years or by Autonomic Regions, although 19.19% of smoker pregnant women quit smoking during the first months of pregnancy. Moreover, the heaviest smoker mothers were the youngest ones in all the years of the study. These results show the need to increase the information for women so that they quit smoking before pregnancy.

[Secular evolution and evolution according to autonomous communities of the frequency of fertility treatments, multiple deliveries and cesarean sections in Spain]. / Evolución secular y por autonomías de la frecuencia de tratamientos de fertilidad, partos múltiples y cesáreas en España.

BACKGROUND AND OBJECTIVE: Fertility treatments, multiple deliveries and caesarean sections are related to maternal age. Because maternal age has increased in Spain, it can also be expected an increase in these variables. We analyzed their evolution over the time and by maternal age, either globally and by Spanish Autonomous Communities. SUBJECTS AND METHOD: We studied a sample of 30,956 mothers of non-malformed newborn infants from all over Spain. STUDY PERIOD: between 1977 and June 2002. RESULTS: The percentage of fertility treatments shows a statistically significant increasing trend in all of the maternal ages groups. However, this was higher in mothers older than 34 years, among whom the frequency of multiple deliveries also increased (p = 0.01). The same trends were observed by Spanish Autonomous Communities, yet with differences between them. In the Comunidad Valenciana, we identified the highest frequency of fertility treatments, while the highest mean maternal age was observed in Aragón. Galicia has one of the lowest proportions of multiple deliveries, while the percentage of fertility treatments is similar to other regions. The percentage of caesarean sections (over 25%, globally) shows a statistically significant increasing trend in all the maternal ages groups, the highest one being among mothers older than 39 years. CONCLUSIONS: The observed increasing maternal age implies a higher use of fertility treatments, multiple deliveries and caesarean sections. All these variables show statistically significant variations between Spanish Autonomous Communities and over the time.

Craniofacial dyssynostosis: description of the first four Spanish cases and review.

Craniofacial dyssynostosis (CD) is characterized by premature fusion of the lambdoid and posterior part of the sagittal sutures, and short stature. Thus, the skull shape becomes dolichocephalic with protuberant forehead and either bulging or flat occiput. Facial changes are secondary to the skull defects, and some additional findings have also been described. We report on the first four known Spanish patients. They were unrelated and had Spanish ancestors. In the three previous reports about this syndrome, the authors hypothesized that the frequency of the gene causing CD must be rather high in the Spanish population, and relatively common in areas with Spanish ancestry. We have estimated the minimal birth prevalence of the syndrome in 0.51 per million livebirths. It has been previously suggested that the syndrome is inherited as an autosomal recessive trait, since there were two affected sisters among the nine published cases. Phenotypic variability is discussed in detail in this paper. We also underline several aspects for the anticipatory guidance of affected individuals, especially recommending a neurologic evaluation taking into account the radiologic findings in order to plan early interventions to avoid undesirable consequences of craniosynostosis. It is also recommended to perform additional studies (ophthalmologic, cardiologic, among others) to rule out the existence of associated anomalies, which are more frequent than previously considered.